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PAP‐1, a Selective Small Molecule Kv1.3 Blocker
Author(s) -
Wulff Heike,
Sankaranaryanan Ananthakrishnan,
Schmitz Alexander,
Azam Philippe,
Hansel Wolfram
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a326
Subject(s) - chemistry , small molecule , pharmacology , herg , selectivity , patch clamp , mixed lymphocyte reaction , receptor , stereochemistry , t cell , potassium channel , medicine , biochemistry , immunology , immune system , catalysis
The lymphocyte K + channel Kv1.3 constitutes an attractive target for the selective suppression of effector memory T (T EM ) cells in autoimmune diseases such as multiple sclerosis, type‐1 diabetes and psoriasis. Unfortunately, all of the existing small molecule Kv1.3 blockers are not selective and many of them like correolide, PAC and our own compound Psora‐4 inhibit the cardiac K + channel Kv1.5. Using Psora‐4 as a template we identified a new series of phenoxyalkoxypsoralens, which exhibit 2 to 50‐fold selectivity for Kv1.3 over Kv1.5. The most potent and “drug‐like” compound of this series, PAP‐1, blocks Kv1.3 with a Hill coefficient of 2 and an EC 50 of 2 nM by preferentially binding to the C‐type inactivated state of the channel. PAP‐1 is 23‐fold selective over Kv1.5, 33 to 125‐fold selective over other Kv1‐family channels and 500 to 7500‐fold selective over Kv2.1, Kv3.1, Kv3.2, Kv4.2, HERG, calcium‐activated K + channels, Na + , Ca 2+ and Cl − channels. PAP‐1 potently inhibits the proliferation of human T EM cells and suppresses delayed type hypersensitivity, a CD4 + T cell mediated reaction, in rats when administered intraperitoneally or orally. PAP‐1 further effectively treats allergic contact dermatitis, a CD8 + T cell mediated reaction. PAP‐1 and several of its derivatives therefore constitute excellent new tools to further explore Kv1.3 as a target for immunosuppression. Supported by NMSS